CCRL2 Promotes the Interferon-γ Signaling Response in Myeloid Neoplasms With Erythroid Differentiation and Mutated TP53

Authors

• Nour Sabiha Naji
• Sergiu Pasca
• Theodora Chatzilygeroudi
• Pablo Toledano-Sanz
• Joseph Rimando
• Yashvi Hemani
• Brandy Perkins
• Xinghan Zeng
• Conover Talbot
• Bogdan Paun
• Abdulmuez Abdulmalik
• Chen Lossos
• Tatianna R Boronina
• Ilias Sinanidis
• Panagiotis Tsakiroglou
• Priyanka Fernandes
• Christopher Esteb
• Alexander J Ambinder
• Robert N Cole
• Rena Xian
• Ivana Gojo
• Suman Paul
• Mark J Levis
• Amy E DeZern
• Leo Luznik
• Styliani Karanika
• Linda S Resar
• Richard J Jones
• Frederick Bunz
• Lukasz Gondek
• Marios Arvanitis
• Theodoros Karantanos

Language

English

Publication Date

2-27-2025

Journal

bioRxiv

DOI

10.1101/2025.02.21.639304

PMID

40060699

PMCID

PMC11888204

PubMedCentral® Posted Date

2-27-2025

PubMedCentral® Full Text Version

Pre-Print

Abstract

Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. The knockout (KO) of CCRL2 suppressed erythroleukemia growth in vitro and in vivo . Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2 driven IFN-γ signaling independent of exogenous IFN-γ, through phosphorylation of STAT1, via JAK2-dependent and independent mechanisms. CCRL2/IFN-γ signaling is upregulated in erythroid leukemias, and TP53 mutated AML without concurrent increase of IFN-γ secretion in the bone marrow microenvironment and is directly induced by TP53 KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms.

Published Open-Access

yes

Recommended Citation

Naji, Nour Sabiha; Pasca, Sergiu; Chatzilygeroudi, Theodora; et al., "CCRL2 Promotes the Interferon-γ Signaling Response in Myeloid Neoplasms With Erythroid Differentiation and Mutated TP53" (2025). Faculty, Staff and Students Publications. 8136.
https://digitalcommons.library.tmc.edu/baylor_docs/8136